Leucine retention in lysosomes is regulated by starvation.
Leucine retention in lysosomes is regulated by starvation.
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DOI：
10.1073/pnas.2114912119
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发表时间：
2022-02-08
影响因子：
11.1
通讯作者：
Overholtzer M
中科院分区：
文献类型：
--
作者：
Bandyopadhyay U;Todorova P;Pavlova NN;Tada Y;Thompson CB;Finley LWS;Overholtzer M
细胞可以通过上调应激反应来应对饥饿，从而促进必需营养素的回收或清除。我们确定了一种饥饿反应，当细胞外氨基酸缺乏时，这种反应允许细胞在溶酶体内储存必需氨基酸亮氨酸。这种“储存”反应允许细胞隔离一种必需氨基酸以支持蛋白质合成。我们发现，许多必需氨基酸被贩运通过溶酶体，即使当细胞外浓度很高，这表明通过溶酶体的组成性通量与饥饿诱导的存储。细胞从环境中获取必需的营养素，并利用适应机制在营养素缺乏时生存。营养物质如何在细胞内运输和划分，以及它们是否在应对压力时储存，仍然知之甚少。在这里，我们调查氨基酸运输和发现证据的溶酶体转运的许多必需氨基酸。我们发现，饥饿诱导的方式需要RAG-GTP酶和溶酶体蛋白复合物Ragulator的亮氨酸的溶酶体保留，但这一过程发生独立的雷帕霉素复合物1活性的机制目标。我们进一步发现，储存的亮氨酸被用于蛋白质合成，抑制蛋白质合成释放溶酶体储存。这些发现确定了一个受调节的饥饿反应，涉及亮氨酸的溶酶体储存。
Cells can respond to starvation by up-regulating stress responses that promote the recycling or scavenging of essential nutrients. We identify a starvation response that allows cells to store the essential amino acid leucine within lysosomes when extracellular amino acids are scarce. This “storage” response allows cells to sequester an essential amino acid in support of protein synthesis. We find that numerous essential amino acids are trafficked through lysosomes even when extracellular concentrations are high, suggesting that constitutive flux through lysosomes is related to starvation-induced storage. Cells acquire essential nutrients from the environment and utilize adaptive mechanisms to survive when nutrients are scarce. How nutrients are trafficked and compartmentalized within cells and whether they are stored in response to stress remain poorly understood. Here, we investigate amino acid trafficking and uncover evidence for the lysosomal transit of numerous essential amino acids. We find that starvation induces the lysosomal retention of leucine in a manner requiring RAG-GTPases and the lysosomal protein complex Ragulator, but that this process occurs independently of mechanistic target of rapamycin complex 1 activity. We further find that stored leucine is utilized in protein synthesis and that inhibition of protein synthesis releases lysosomal stores. These findings identify a regulated starvation response that involves the lysosomal storage of leucine.
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影响因子：
16
作者：
Sengupta S;Peterson TR;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
64.8
作者：
Palm W;Thompson CB
通讯作者：
Thompson CB
MTORC1抑制了细胞外蛋白作为养分的利用。
影响因子：
64.5
作者：
Palm W;Park Y;Wright K;Pavlova NN;Tuveson DA;Thompson CB
通讯作者：
Thompson CB
影响因子：
13.3
作者：
Aits, Sonja;Kricker, Jennifer;Jaattela, Marja
通讯作者：
Jaattela, Marja
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS